Effect of Secreted Frizzled-Related Protein 2 (sFRP2) from Adipose Tissue on Pancreatic Cell Function

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 697-707-Obesity Pathophysiology
Translational
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-700
Iwona Bujalska*1, Elizabeth Helen Rabbitt2, Danielle Foucault2, Jeremy W Tomlinson1 and Paul Michael Stewart2
1University of Birmingham, United Kingdom, 2University of Birmingham, Birmingham, United Kingdom
The detrimental effect of excessive obesity on insulin resistance is well established.  The expansion of adipose tissue (AT) is dependent on two processes: adipogenesis and angiogenesis and the Wnt signalling pathway has been reported to affect both.  In AT the Wnt signalling pathway functions in a converse manner: increasing commitment of mesenchymal stem cells to preadipocytes and inhibiting differentiation of preadipocytes to mature adipocytes by decreasing expression of CEBPa and PPARg.  One of the antagonists of the canonical Wnt signalling pathway is secreted frizzled-related protein 2 (sFRP2) however, recent studies have identified sFRP2 as a novel factor stimulating angiogenesis via a non-canonical, calcineurin/NFAT signalling pathway. Expression of sFRP2 and Wnt receptors, Fzd1 and Fzd2, mRNA has been reported in preadipocytes and Wnt signalling is also known to be involved in pancreatic islet function, insulin production and secretion.  We hypothesised that sFRP2 secreted from AT could provide a link between obesity and diabetes through a deleterious action on b-cells/insulin secretion. Human omental (OM) and subcutaneous (SC) AT expressed high levels of sFRP2 mRNA; 6.9-fold higher in OM than SC depots (SC DCt=15.62 vs OM DCt=12.82, p<0.01, n=4).  Similarly, 63% more sFRP2 protein was secreted from human OM than SC AT explants (p=0.008, n=5). In humans, we observed higher sFRP2 concentrations in serum of diabetic patients compared to normal (diabetic: 7.47+/-3.1 vs normal: 3.04+/-1.16 mean+/-sd, p<0.05, n=6). In mice, sFRP2 mRNA was present in gonadal and SC fats but absent in liver, pancreas and pancreatic a- and b-cell lines.  Significantly, proliferating mouse pancreatic a- and b-cells treated with recombinant mouse sFRP2 protein (10ng to 200ng/ml) for 4 days, showed a dose-dependent decrease in proliferation rates in b-cells (10ng/ml: 96%, 100ng/ml: 84%, 200ng/ml: 72% vs 100% control, p<0.01) but not a-cells or the human preadipocyte cell line, ChubS7. Furthermore, treatment with 200ng/ml sFRP2 protein decreased insulin secretion from MIN6 cells by 41.5%, p<0.01, n=3.  We postulate that secreted sFRP2 from expanding AT (especially OM) could have a harmful effect on pancreatic b-cell function and contribute to the pathogenesis of insulin resistance in human obesity.

Nothing to Disclose: IB, EHR, DF, JWT, PMS

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